Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells.
Ubiquitin-dependent protein degradation is involved in various biological processes, and accumulating evidence suggests that E3 ubiquitin ligases play important roles in cancer development. Smad ubiquitin regulatory factor 1 (Smurf1) and Smurf2 are E3 ubiquitin ligases, which suppress transforming growth factor-beta (TGF-beta) family signaling through degradation of Smads and receptors for TGF-beta and bone morphogenetic proteins. In addition, Smurf1 has been reported to promote RhoA ubiquitination and degradation and regulate cell motility, suggesting the involvement of Smurf1 in cancer progression. However, the regulation and biological function of Smurf1 and Smurf2 in cancer development remain to be elucidated. In the present study, we show the post-translational regulation of Smurf1 by Smurf2 and the functional differences between Smurf1 and Smurf2 in the progression of breast cancer cells. Smurf2 interacted with Smurf1 and induced its ubiquitination and degradation, whereas Smurf1 failed to induce degradation of Smurf2. Knockdown of Smurf2 in human breast cancer MDA-MB-231 cells resulted in increases in the levels of Smurf1 protein, and enhancement of cell migration in vitro and bone metastasis in vivo. Of note, knockdown of Smurf1, but not of Smurf2, enhanced TGF-beta signaling in MDA-MB-231 cells, suggesting that increased an protein level of Smurf1 offsets the effect of Smurf2 knockdown on TGF-beta signaling. These results indicate that two related E3 ubiquitin ligases, Smurf1 and Smurf2, act in the same direction in TGF-beta family signaling but play opposite roles in cell migration.
Fukunaga
Erina
E
Department of Biochemistry, Cancer Institute of the Japanese Foundation for Cancer Research, 135-8550 Tokyo, Japan.
Inoue
Yasumichi
Y
Komiya
Setsuro
S
Horiguchi
Kana
K
Goto
Kouichiro
K
Saitoh
Masao
M
Miyazawa
Keiji
K
Koinuma
Daizo
D
Hanyu
Aki
A
Imamura
Takeshi
T
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C498342:SMURF1 protein, human; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases